Abstract
The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.
Highlights
Chronic kidney disease (CKD) affects 30 million people in the United States [1], and it is the twelfth most common cause of death worldwide, accounting for over one million deaths [2]
We demonstrated a significant reduction in both circulating PON-1 protein and PON lactonase activity from a large cohort of CKD patients compared to a reference non-CKD
Our findings indicate that decreased circulating PON lactonase activity was predictive of future all-cause mortality in this CKD cohort
Summary
Chronic kidney disease (CKD) affects 30 million people in the United States [1], and it is the twelfth most common cause of death worldwide, accounting for over one million deaths [2]. Paraoxonases (PON) are a family of hydrolytic enzymes that include three distinct isoforms: PON-1, PON-2, and PON-3 These enzymes are highly conserved, sharing 60–70% nucleic acid homology. PON-1’s association with HDL protects HDL from oxidative modifications and is responsible for much of HDL’s antioxidant, anti-inflammatory, and anti-atherogenic properties, such as protecting low-density lipoprotein (LDL) from oxidation, macrophage cholesterol efflux, and reverse cholesterol transport [19]. These anti-atherogenic mechanisms aid in preventing macrophage cholesterol accumulation and have been the focus of significant research
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